Pathogenic analysis of the pandemic 2009 H1N1 influenza A viruses in ferrets
Identifieur interne : 000B45 ( Pmc/Corpus ); précédent : 000B44; suivant : 000B46Pathogenic analysis of the pandemic 2009 H1N1 influenza A viruses in ferrets
Auteurs : Yoshimi Tsuda ; Carla Weisend ; Cynthia Martellaro ; Friederike Feldmann ; Elaine HaddockSource :
- The Journal of Veterinary Medical Science [ 0916-7250 ] ; 2017.
Abstract
The pandemic 2009 H1N1 influenza A virus emerged in humans and caused the first influenza pandemic of the 21st century. Mexican isolates, A/Mexico/4108/2009 (H1N1) (Mex4108) and A/Mexico/InDRE4478/2009 (H1N1) (Mex4487) derived from a mild case and from a cluster of severe cases, showed heterogeneity in virulence in a cynomolgus macaque model. To compare the more pathogenic differences, we generated recombinant viruses and compared their virulence in ferrets. Ferrets infected with recombinant Mex4487 displayed a slightly higher rate of viral replication and severe pneumonia in the early stage of infection. In contrast, prolonged lower virus shedding of recombinant Mex4108 than that of recombinant Mex4487 was detected in throat swabs. Thus, Mex4487 induces severe pneumonia in infected individuals, whereas Mex4108 might have wide-spreading potential with mild disease.
Url:
DOI: 10.1292/jvms.16-0619
PubMed: 28674309
PubMed Central: 5573836
Links to Exploration step
PMC:5573836Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Pathogenic analysis of the pandemic 2009 H1N1 influenza A viruses in
ferrets</title><author><name sortKey="Tsuda, Yoshimi" sort="Tsuda, Yoshimi" uniqKey="Tsuda Y" first="Yoshimi" last="Tsuda">Yoshimi Tsuda</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Weisend, Carla" sort="Weisend, Carla" uniqKey="Weisend C" first="Carla" last="Weisend">Carla Weisend</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Martellaro, Cynthia" sort="Martellaro, Cynthia" uniqKey="Martellaro C" first="Cynthia" last="Martellaro">Cynthia Martellaro</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Feldmann, Friederike" sort="Feldmann, Friederike" uniqKey="Feldmann F" first="Friederike" last="Feldmann">Friederike Feldmann</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Haddock, Elaine" sort="Haddock, Elaine" uniqKey="Haddock E" first="Elaine" last="Haddock">Elaine Haddock</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">28674309</idno><idno type="pmc">5573836</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5573836</idno><idno type="RBID">PMC:5573836</idno><idno type="doi">10.1292/jvms.16-0619</idno><date when="2017">2017</date><idno type="wicri:Area/Pmc/Corpus">000B45</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000B45</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Pathogenic analysis of the pandemic 2009 H1N1 influenza A viruses in
ferrets</title><author><name sortKey="Tsuda, Yoshimi" sort="Tsuda, Yoshimi" uniqKey="Tsuda Y" first="Yoshimi" last="Tsuda">Yoshimi Tsuda</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Weisend, Carla" sort="Weisend, Carla" uniqKey="Weisend C" first="Carla" last="Weisend">Carla Weisend</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Martellaro, Cynthia" sort="Martellaro, Cynthia" uniqKey="Martellaro C" first="Cynthia" last="Martellaro">Cynthia Martellaro</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Feldmann, Friederike" sort="Feldmann, Friederike" uniqKey="Feldmann F" first="Friederike" last="Feldmann">Friederike Feldmann</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author><author><name sortKey="Haddock, Elaine" sort="Haddock, Elaine" uniqKey="Haddock E" first="Elaine" last="Haddock">Elaine Haddock</name><affiliation><nlm:aff>NONE</nlm:aff></affiliation></author></analytic><series><title level="j">The Journal of Veterinary Medical Science</title><idno type="ISSN">0916-7250</idno><idno type="eISSN">1347-7439</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The pandemic 2009 H1N1 influenza A virus emerged in humans and caused the first influenza
pandemic of the 21st century. Mexican isolates, A/Mexico/4108/2009 (H1N1) (Mex4108) and
A/Mexico/InDRE4478/2009 (H1N1) (Mex4487) derived from a mild case and from a cluster of
severe cases, showed heterogeneity in virulence in a cynomolgus macaque model. To compare
the more pathogenic differences, we generated recombinant viruses and compared their
virulence in ferrets. Ferrets infected with recombinant Mex4487 displayed a slightly
higher rate of viral replication and severe pneumonia in the early stage of infection. In
contrast, prolonged lower virus shedding of recombinant Mex4108 than that of recombinant
Mex4487 was detected in throat swabs. Thus, Mex4487 induces severe pneumonia in infected
individuals, whereas Mex4108 might have wide-spreading potential with mild disease.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Barnard, D L" uniqKey="Barnard D">D. L. Barnard</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chowell, G" uniqKey="Chowell G">G. Chowell</name></author><author><name sortKey="Bertozzi, S M" uniqKey="Bertozzi S">S. M. Bertozzi</name></author><author><name sortKey="Colchero, M A" uniqKey="Colchero M">M. A. Colchero</name></author><author><name sortKey="Lopez Gatell, H" uniqKey="Lopez Gatell H">H. Lopez-Gatell</name></author><author><name sortKey="Alpuche Aranda, C" uniqKey="Alpuche Aranda C">C. Alpuche-Aranda</name></author><author><name sortKey="Hernandez, M" uniqKey="Hernandez M">M. Hernandez</name></author><author><name sortKey="Miller, M A" uniqKey="Miller M">M. A. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">J Vet Med Sci</journal-id><journal-id journal-id-type="iso-abbrev">J. Vet. Med. Sci</journal-id><journal-id journal-id-type="publisher-id">JVMS</journal-id><journal-title-group><journal-title>The Journal of Veterinary Medical Science</journal-title></journal-title-group><issn pub-type="ppub">0916-7250</issn><issn pub-type="epub">1347-7439</issn><publisher><publisher-name>The Japanese Society of Veterinary Science</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">28674309</article-id><article-id pub-id-type="pmc">5573836</article-id><article-id pub-id-type="publisher-id">16-0619</article-id><article-id pub-id-type="doi">10.1292/jvms.16-0619</article-id><article-categories><subj-group subj-group-type="heading"><subject>Virology</subject><subj-group><subject>Full Paper</subject></subj-group></subj-group></article-categories><title-group><article-title>Pathogenic analysis of the pandemic 2009 H1N1 influenza A viruses in
ferrets</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>TSUDA</surname><given-names>Yoshimi</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff3"><sup>3</sup></xref><xref rid="cor1" ref-type="corresp"><sup>*</sup></xref></contrib><contrib contrib-type="author"><name><surname>WEISEND</surname><given-names>Carla</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>MARTELLARO</surname><given-names>Cynthia</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>FELDMANN</surname><given-names>Friederike</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>HADDOCK</surname><given-names>Elaine</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><aff id="aff1"><label>1)</label>Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, U.S.A.</aff><aff id="aff2"><label>2)</label>Rocky Mountain Veterinary Branch, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, U.S.A.</aff><aff id="aff3"><label>3)</label>Present address: Department of Microbiology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan</aff></contrib-group><author-notes><corresp id="cor1"><label>*</label>Correspondence to: Tsuda, Y.: <email xlink:href="yoshimi.tsuda@nih.gov">yoshimi.tsuda@nih.gov</email></corresp></author-notes><pub-date pub-type="epub"><day>03</day><month>7</month><year>2017</year></pub-date><pub-date pub-type="ppub"><month>8</month><year>2017</year></pub-date><volume>79</volume><issue>8</issue><fpage>1453</fpage><lpage>1460</lpage><history><date date-type="received"><day>29</day><month>11</month><year>2016</year></date><date date-type="accepted"><day>19</day><month>6</month><year>2017</year></date></history><permissions><copyright-statement>©2017 The Japanese Society of Veterinary Science</copyright-statement><copyright-year>2017</copyright-year><license license-type="open-access"><license-p>This is an open-access article distributed under the terms of the Creative
Commons Attribution Non-Commercial No Derivatives (by-nc-nd) License. (CC-BY-NC-ND 4.0:
<ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/licenses/by-nc-nd/4.0/">https://creativecommons.org/licenses/by-nc-nd/4.0/</ext-link>)</license-p></license></permissions><abstract><p>The pandemic 2009 H1N1 influenza A virus emerged in humans and caused the first influenza
pandemic of the 21st century. Mexican isolates, A/Mexico/4108/2009 (H1N1) (Mex4108) and
A/Mexico/InDRE4478/2009 (H1N1) (Mex4487) derived from a mild case and from a cluster of
severe cases, showed heterogeneity in virulence in a cynomolgus macaque model. To compare
the more pathogenic differences, we generated recombinant viruses and compared their
virulence in ferrets. Ferrets infected with recombinant Mex4487 displayed a slightly
higher rate of viral replication and severe pneumonia in the early stage of infection. In
contrast, prolonged lower virus shedding of recombinant Mex4108 than that of recombinant
Mex4487 was detected in throat swabs. Thus, Mex4487 induces severe pneumonia in infected
individuals, whereas Mex4108 might have wide-spreading potential with mild disease.</p></abstract><kwd-group><kwd>ferret</kwd><kwd>pathogenesis</kwd><kwd>virus shedding</kwd></kwd-group></article-meta></front><body><p>Influenza A virus infections in humans are typically associated with limited seasonal
outbreaks of commonly circulating influenza virus strains (seasonal strains). A new virus
strain occasionally emerges in humans, resulting in increased morbidity and mortality compared
to those of seasonal influenza (pandemic strain) [<xref rid="r29" ref-type="bibr">29</xref>].
A novel H1N1 influenza A virus, the pandemic 2009 H1N1 influenza A virus (A(H1N1) pdm2009),
caused the first human influenza pandemic of the new millennium [<xref rid="r3" ref-type="bibr">3</xref>, <xref rid="r4" ref-type="bibr">4</xref>, <xref rid="r6" ref-type="bibr">6</xref>]. In 2010, WHO announced that A(H1N1) pdm2009 had moved into the post-pandemic
period [<xref rid="r27" ref-type="bibr">27</xref>, <xref rid="r28" ref-type="bibr">28</xref>].
A(H1N1) pdm2009 has now replaced the classical seasonal H1N1 strains and is circulating
globally as a current seasonal strain with a case fatality rate similar to that of classical
seasonal influenza.</p><p>Human pandemic A(H1N1) pdm2009 infections appeared to be mild in general, and some infected
individuals presented with symptoms atypical for seasonal influenza; however, severe illness
was also reported, particularly in young, previously healthy individuals [<xref rid="r2" ref-type="bibr">2</xref>, <xref rid="r3" ref-type="bibr">3</xref>, <xref rid="r21" ref-type="bibr">21</xref>]. Several early isolates also caused severe diseases in
experimentally infected animals, and pathogenicity factors were analyzed [<xref rid="r9" ref-type="bibr">9</xref>, <xref rid="r13" ref-type="bibr">13</xref>, <xref rid="r16" ref-type="bibr">16</xref>]. Interestingly, many severe cases of seasonal A(H1N1)
pdm2009 were reported in Mexico during the 2013–2014 influenza season [<xref rid="r14" ref-type="bibr">14</xref>]. There is the possibility that antigenic change of HA is a reason for
middle-aged adults being highly susceptible to seasonal A(H1N1) pdm2009 in the 2013–2014
influenza season [<xref rid="r12" ref-type="bibr">12</xref>]. Thus, several factors associated
in virulence and human adaptation factors of viruses have identified, and it is still
important to accumulate knowledge of the pathogenic potential and analyze the potential
virulence factors of these influenza viruses.</p><p>In our previous study, infection of cynomolgus macaques with two genetically similar but
clinically distinct human A(H1N1) pdm2009 strains, A/Mexico/4108/2009 (Mex4108) and
A/Mexico/InDRE4487/2009 (Mex4487), isolated during the early phase of the pandemic [<xref rid="r23" ref-type="bibr">23</xref>], resulted in higher pathogenic potential of Mex4487. To
investigate the potential virulence of Mexican isolates, we generated recombinant viruses
between the two Mexican A(H1N1) pdm2009 isolates and evaluated their pathogenicity in the
ferret model, a widely used and well-established model for studying both the pathogenicity and
transmissibility of human influenza viruses [<xref rid="r1" ref-type="bibr">1</xref>, <xref rid="r26" ref-type="bibr">26</xref>].</p><sec sec-type="materials|methods" id="s1"><title>MATERIALS AND METHODS</title><sec><title>Cells</title><p>Madin-Darby canine kidney (MDCK) cells were maintained in Eagle’s minimum essential
medium (MEM) supplemented with 10% fetal bovine serum (FBS), 2 mM L-glutamine and
penicillin/streptomycin (Pen/St). Human lung carcinoma (A549) and human embryonic kidney
293T cells were maintained in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with
10% FBS, 2 mM L-glutamine and Pen/St.</p></sec><sec><title>Viruses</title><p>Influenza viruses, Mex4108 (kindly provided by the Centers for Disease Control and
Prevention, Atlanta, GA, U.S.A.) and Mex4487 (kindly provided by Public Health Agency of
Canada, Winnipeg, MB, Canada), as well as the recombinant viruses, were propagated in MDCK
cells with MEM containing 2% FBS and 0.35 <italic>µ</italic>g/m<italic>l</italic> of TPCK
(tolylsulfonyl phenylalanyl chloromethyl ketone)-trypsin. Virus infectivity titers were
determined using the 50% tissue culture infectious dose (TCID50) assay. For this assay,
10-fold dilutions of supernatants were used to infect MDCK cells. The virus-induced
cytopathogenic effect (CPE) was scored at 3 days post-infection (dpi).</p></sec><sec><title>Generation of recombinant viruses</title><p>Genomic RNA of Mex4108 and Mex4487 was extracted from virus stocks and used to amplify
the eight gene segments by reverse transcription-polymerase chain reaction (RT-PCR). Each
PCR product was individually cloned into a polI-promoter plasmid (ppolI) [<xref rid="r18" ref-type="bibr">18</xref>]. The open reading frames coding for components of
the influenza virus RNP complex, polymerase basic protein 2 (PB2), polymerase basic
protein 1 (PB1), polymerase acidic protein (PA) and nucleoprotein (NP), were cloned into
the expression plasmid pCAGGs (helper plasmids). All plasmids were sequence confirmed
prior to use. To generate recombinant viruses, different combinations of the eight ppolI
plasmids from either Mex4108 or Mex4487 were transfected together with the four helper
plasmids into 293T cells. After 30 hr of incubation, transfection supernatants were
removed, and OPTI-MEM with TPCK trypsin was added. At 48 hr post-transfection (hpt), the
supernatant was collected, and the rescued virus was subsequently propagated in MDCK
cells. All rescued recombinant viruses were sequence confirmed, and virus titers were
determined by a standard TCID50 assay in MDCK cells (<xref rid="tbl_001" ref-type="table">Table 1</xref><table-wrap id="tbl_001" orientation="portrait" position="float"><label>Table 1.</label><caption><title>Recombinant viruses generated by a reverse genetics system</title></caption><graphic xlink:href="jvms-79-1453-t001"></graphic></table-wrap>). Recombinant viruses, rgMex4108 and rgMex4487, rescued with titers similar
to those of the original isolates.</p></sec><sec><title>In vitro growth kinetics of recombinant viruses</title><p>Confluent monolayers of A549 and MDCK cells were inoculated with rgMex4108, rgMex4487,
rgM4108/M4487-HA.NP.M, rgM4108/M4487-PA.PB2, rgM4108/M4487-PB2 or rgM4108/M4487-PA at a
multiplicity of infection (MOI) of 0.1 (A549 cells) or 0.001 (MDCK cells). Virus was
allowed to adsorb for 1 hr, then unbound viruses were washed away, and DMEM or MEM with
TPCK-trypsin was added. At determined time points, the supernatants were collected from 3
wells per virus. Virus titers were determined as TCID50 on MDCK cells.</p></sec><sec><title>Animal study</title><p>Groups of 12 ferrets (females, 4–12 months, weight range: 630 to 990 g) were inoculated
with rgMex4487 or rgMex4108 (10<sup>6</sup> TCID50/ferret) via the intranasal or
intratracheal route, and the animals were monitored daily for body weight and signs of
disease for 14 days. Four animals from each group were euthanized at 3 or 6 dpi, and
tissue samples were collected for virology and histopathological evaluation. Tissues were
placed in cassettes and fixed in 10% Neutral Buffered Formalin x2 changes, for a minimum
of 7 days. Cassettes were processed with a Sakura Tissue-Tek VIP-6, on a 12 hr automated
schedule, using a graded series of ethanol, xylene and Ultraffin-X paraffin. Embedded
tissues are sectioned at 5 <italic>µ</italic>m and dried overnight at 42°C prior to
staining. Tissues were stained by hematoxylin and eosin (H&E) stain and scored as:
0=no, 1=minimal, 2=mild, 3=moderate, 4=marked and 5=severe lesion. Infectivity of the
virus was determined as TCID50. All animal experiments were approved by the Institutional
Animal Care and Use Committee of Rocky Mountain Laboratories and performed following the
guidelines of the Association for Assessment and Accreditation of Laboratory Animal Care,
International (AAALAC) by certified staff in an AAALAC-approved facility.</p></sec><sec><title>Biosafety</title><p>All infectious <italic>in vitro</italic> and <italic>in vivo</italic> studies were
performed in high biocontainment at the Integrated Research Facility (IRF) of Rocky
Mountain Laboratories (RML), Division of Intramural Research (DIR), National Institute of
Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). Sample
inactivation and removal from the containment facility was performed according to standard
operating protocols approved by the local Institutional Biosafety Committee.</p></sec><sec><title>Statistical analysis</title><p>Statistical analyses were performed using a two-tailed Student’s
<italic>t</italic>-test.</p></sec></sec><sec sec-type="results" id="s2"><title>RESULTS</title><sec><title>Growth kinetics of recombinant viruses</title><p>A comparison of the two Mexican isolates, rgMex4108 and rgMex4487, revealed a difference
in seven amino acids affecting five proteins [PB2 (amino acid position (aa) 82) and PA
(aa275, aa581), HA (aa444), NP (aa100, aa373) and M2 protein (aa82)] [<xref rid="r23" ref-type="bibr">23</xref>]. We generated rgMex4108, rgMex4487 and other 4
recombinant viruses of which two were single-gene replacements (PB2, PA), a dual-gene
replacement of PB2 and PA and a triple-gene replacement of HA, NP and M. The titers of the
all rescued recombinant viruses ranged from 10<sup>6.0</sup> to 10<sup>7.3</sup>TCID50/m<italic>l</italic> (<xref rid="tbl_001" ref-type="table">Table 1</xref>).
<italic>In vitro</italic> growth kinetics was performed in A549 cells infected with a
MOI of 0.1. As shown in <xref ref-type="fig" rid="fig_001">Fig. 1A</xref><fig orientation="portrait" fig-type="figure" id="fig_001" position="float"><label>Fig. 1.</label><caption><p><italic>In vitro</italic> growth kinetics of recombinant viruses. Confluent A549
(A) or MDCK (B) cells were infected with recombinant viruses, rgMex4108, rgMex4487,
M4108/M4487-PB2.PA, M4108/M4487-HA.NP.M, M4108/M4487-PB2 or M4108/M4487-PA at a MOI
of 0.1 (A549) or 0.001 (MDCK), respectively. Infected cells were incubated at 37°C,
and supernatants were collected at the indicated times. Virus titer of supernatants
was expressed as TCID50 with standard deviations (S.D.).</p></caption><graphic xlink:href="jvms-79-1453-g001"></graphic></fig>, rgMex4487 showed approximately 1 log higher replication compared to rgMex4108 at
12 hr post-inoculation (hpi). Mex4108 backbone viruses of which PA and/or PB2 genes are
from Mex4487 (white symbols) tended to higher replication than rgMex4108 or
rgM4108/M4487-HA.NP.M (black symbols), however, no significant difference was observed. We
also evaluated the growth kinetics in MDCK cells that was used for virus propagation. All
recombinant viruses replicated similarly over a time course of 72 hr with no significant
differences in titers and reached highest virus titer at 48 hpi as similar in <xref rid="tbl_001" ref-type="table">Table 1</xref> (<xref ref-type="fig" rid="fig_001">Fig.
1B</xref>).</p></sec><sec><title>Pathogenicity of recombinant viruses in ferrets</title><p>Ferrets were inoculated with rgMex4487 or rgMex4108 via the intranasal (<xref ref-type="fig" rid="fig_002">Fig. 2A and 2B</xref><fig orientation="portrait" fig-type="figure" id="fig_002" position="float"><label>Fig. 2.</label><caption><p>Comparison of pathogenicities of recombinant viruses. Ferrets were infected with a
dose of 10<sup>6</sup> TCID50 of either rgMex4108 or rgMex4487 via the intranasal
(A, B) or intratracheal (C, D) route. (A, C) Body weight loss of ferrets was
monitored until 14 dpi. (B, D) Virus shedding in swabs was monitored until 14 dpi.
Black symbols indicate Mex4108, and white symbols indicate Mex4487.</p></caption><graphic xlink:href="jvms-79-1453-g002"></graphic></fig>) or intratracheal (<xref ref-type="fig" rid="fig_002">Fig. 2C and
2D</xref>) route. Both groups developed only mild clinical symptoms, and all of the
ferrets survived except for two ferrets inoculated with rgMex4108 via the intratracheal
route. Those two ferrets died at 2 and 9 dpi with suspected secondary bacterial infection
(<xref ref-type="supplementary-material" rid="pdf_001">Supplemental Fig. 1</xref>).</p><p>By the intranasal inoculation route, no weight loss was induced in either of the groups
(<xref ref-type="fig" rid="fig_002">Fig. 2A</xref>). Virus shedding in nasal and throat
swabs was monitored every other day until 14 dpi. rgMex4487 reached the highest titer of 5
× 10<sup>5</sup> TCID50/m<italic>l</italic> at 1 dpi from throat swabs, and then, the
virus titer decreased (<xref ref-type="fig" rid="fig_002">Fig. 2B</xref>). In contrast,
the titer of rgMex4108 in throat swabs remained at 10<sup>4</sup>TCID50/m<italic>l</italic> until 5 dpi. The virus titers in nasal swab were similar in
the two groups. Ferrets inoculated with viruses via the intratracheal route exhibited mild
weight loss until 7 dpi in both groups and subsequently recovered (<xref ref-type="fig" rid="fig_002">Fig. 2C</xref>). As was observed in the groups with intranasal
inoculation, the highest virus titer of rgMex4487 was detected at 1 dpi from throat swabs
(<xref ref-type="fig" rid="fig_002">Fig. 2D</xref>). The virus titer of rgMex4108 in
throat swabs increased and reached 10<sup>5</sup> TCID50 at 5 dpi, but no significant
difference was observed in all time points. The virus titers in nasal swab were similar in
the two groups.</p></sec><sec><title>Histopathological differences of recombinant viruses</title><p>We next compared the viral replication and histopathological changes in respiratory
tissues. Four animals from each group were euthanized at 3 or 6 dpi, and tissue samples
were collected. By the intranasal inoculation, the highest rate of virus replication was
detected in all respiratory tissues at 3 dpi (<xref ref-type="fig" rid="fig_003">Fig.
3A</xref><fig orientation="portrait" fig-type="figure" id="fig_003" position="float"><label>Fig. 3.</label><caption><p>Comparison of pathological differences in ferrets. Ferrets were infected with a
dose of 10<sup>6</sup> TCID50 of either rgMex4108 or rgMex4487 via the intranasal
(A, C, E) or intratracheal (B, D, F) route. Four ferrets were euthanized at 3 or 6
dpi. (A, B) Virus titers of respiratory tissues are shown as TCID50 with S.D. (C, D)
Histopathological data are shown as the average of pathological scores with S.D.
*<italic>P</italic><0.05. (E, F) Histpathological sections of lung tissues were
stained with H&E stain, original magnification ×100. Black symbols indicate
Mex4108, and white symbols indicate Mex4487.</p></caption><graphic xlink:href="jvms-79-1453-g003"></graphic></fig>). Although virus titers of rgMex4487 were slightly higher than those of rgMex4108
at 3 dpi in most of the respiratory tissues tested, no significant differences were
observed. Virus replication decreased by 6 dpi in all respiratory tissues. Ferrets
inoculated with rgMex4487 had developed severe inflammation and pneumonia on day
3 (<xref ref-type="fig" rid="fig_003">Fig. 3C and 3E</xref>). Mild
inflammation and pneumonia were still observed in all respiratory tissues at 6 dpi, even
though the virus replication on day 6 was lower than on day 3. Ferrets inoculated with
viruses via the intratracheal route showed more severe pneumonia at 3 dpi compared with
ferrets inoculated with viruses via the intranasal route (<xref ref-type="fig" rid="fig_003">Fig. 3D and 3F</xref>). The high rate of virus replication was detected in
respiratory tissues at 3 dpi and continued through 6 dpi (<xref ref-type="fig" rid="fig_003">Fig. 3B</xref>). Although moderate pneumonia was detected in both groups
until day 6, rgMex4108 seemed to replicate well in respiratory tissues without severe
inflammation, as compared to rgMex4487. All four groups of ferrets developed multifocal,
moderate to marked bronchointerstitial pneumonia; however, ferrets inoculated via the
intratracheal route tended to have more severe lesions. Pulmonary changes are
predominately centered on terminal bronchioles, but often extend into adjacent bronchi and
surrounding alveoli (<xref ref-type="fig" rid="fig_003">Fig. 3E and 3F</xref>).</p></sec></sec><sec sec-type="discussion" id="s3"><title>DISCUSSION</title><p>Since the pandemic of 2009, A(H1N1) pdm2009 circulating worldwide as seasonal flu has
caused mild respiratory illness in infected individuals. A(H1N1) pdm2009 has occasionally
caused severe disease and related deaths depending on the virus or the patient’s condition
[<xref rid="r2" ref-type="bibr">2</xref>, <xref rid="r4" ref-type="bibr">4</xref>, <xref rid="r14" ref-type="bibr">14</xref>, <xref rid="r19" ref-type="bibr">19</xref>, <xref rid="r21" ref-type="bibr">21</xref>]. In our previous study, we characterized two Mexican
isolates, Mex4108 and Mex4487, derived from a mild case and from a cluster of severe cases,
respectively. They also produced heterogeneity in virulence in a cynomolgus macaque model
[<xref rid="r23" ref-type="bibr">23</xref>]. However, in this study, experimental
infection with both rgMex4108 and rgMex4487 caused only mild and undistinguishable
respiratory diseases in ferrets. Ferrets inoculated with original isolates also showed mild
symptoms, as was observed by the recombinant viruses (data not shown). In this experiment,
we compared both intranasal and intratracheal inoculation routes, and ferrets inoculated via
the intratracheal route showed slightly reduced body weight by day 7 post-infection and
tended to have more severe lesions by histopathological analysis. However, ferrets showed
similar mild symptom in all groups. We did not find the significant clinical differences
between the two isolates that were observed in the cynomolgus macaque model. The ferret is a
common animal model for an influenza virus study. However, animal models do not always seem
to mimic symptoms that were observed in human cases. To evaluate the pathogenicity
difference of two Mexican isolates, we may need to use the cynomolgus macaque model, since
cynomolgus macaque demonstrated similar clinical differences reflecting human cases in the
previous study. On the other hand, it has been reported that Mex4487-infected ferrets showed
severe clinical signs and that approximately 50% of the animals succumbed to infection
within 9 dpi [<xref rid="r11" ref-type="bibr">11</xref>, <xref rid="r15" ref-type="bibr">15</xref>]. This difference indicates that the outcome of disease might be affected by
rearing environments of infected hosts as well as technical differences of experiments.
However, rgMex4108 yielded a higher and more prolonged virus shedding in throat swabs, and a
higher virus replication was detected until 5 dpi in throat swab. Although there is also no
significant difference between viruses in our ferret model, these results suggested that
Mex4108 may have the potential for long and wide spreading of viruses. To compare the
transmissibility of viruses, contact transmission experiments are required.</p><p>A(H1N1) pdm2009 lacks amino acid mutations previously identified as human adaptation
signature, like PB2-E627K and D701N, and these known virulence associated mutations in PB2
increased reporter gene expression, but did not affect virus replication and transmission
[<xref rid="r8" ref-type="bibr">8</xref>]. Whereas, several A(H1N1) pdm2009 strains
possessing amino acid substitutions in PB2 and HA showed enhanced virulence and transmission
in ferret models [<xref rid="r10" ref-type="bibr">10</xref>, <xref rid="r31" ref-type="bibr">31</xref>, <xref rid="r34" ref-type="bibr">34</xref>]. However, both Mex4487 and Mex4108
do not have identified amino acid sequence that was contributed to virulence and
transmission of viruses in animal models. Only 7 amino acid differences were identified in
the genome of two Mexican isolates. During pandemic period, frequency of specific amino
acids in A(H1N1) pdm2009 circulating in the world had evolved and selected the more
efficient replication and transmissible strains as current seasonal strains [<xref rid="r20" ref-type="bibr">20</xref>]. We also compared the sequences of Mexican isolates
with consensus sequence with A(H1N1) pdm2009 isolated in the early stage of pandemic, and
five of seven amino acid differences are specific for either Mex4108 or Mex4487. Two amino
acid residues in PB2-N82A and PA-L275I of Mex4487, and three amino acid residues in
HA-V444I, NP-D100G and M2-S82N of Mex4108 were specific in each strain. The other two amino
acid differences, PA-581L and NP-373I in Mex4108, were found as common in A(H1N1) pdm2009,
especially in the early stage of pandemic [<xref rid="r20" ref-type="bibr">20</xref>].
Specific mutations in Mex4487 or Mex4108 might affect difference in virulence or
transmissibility of the two isolates.</p><p>The results of <italic>in vitro</italic> growth kinetics of recombinant viruses suggested
that PB2 or PA of Mex4487 is a potential factor for prolonged virus replication in human
alveolar epithelial cells. rgMex4108 possessing PA and/or PB2 of Mex4487 showed a higher
rate of replication than that of rgMex4108. PB2 and PA are components of the RNA-dependent
RNA polymerase complex of influenza A virus, and mutations in PB2 [<xref rid="r7" ref-type="bibr">7</xref>, <xref rid="r32" ref-type="bibr">32</xref>, <xref rid="r33" ref-type="bibr">33</xref>] or PA [<xref rid="r5" ref-type="bibr">5</xref>, <xref rid="r22" ref-type="bibr">22</xref>, <xref rid="r24" ref-type="bibr">24</xref>] associated with host range
or viral pathogenicity have been reported. To determine the functional differences of two
Mexican isolates, we analyzed the polymerase activity and inhibitory effects of IFN
induction of both RNP complexes derived from Mex4108 or Mex4487 using a reporter assay.
However, no difference was observed in both assays tested (<xref ref-type="supplementary-material" rid="pdf_001">Supplemental Fig. 2</xref>). We evaluated the polymerase activity in human cell lines,
A549 and 293, and polymerase activities were similar for any combination of the RNP complex
derived from Mex4108 or Mex4487. As another function of PB2, we also compared the inhibition
activity of MAVS-mediated IFN-β induction. From the IFN-β promoter-driven reporter assay,
significant inhibition of MAVS-mediated IFN-β induction by both PB2 and PA was observed.
However, again, no difference was observed in this activity between proteins derived from
Mex4108 or Mex4487 (<xref ref-type="supplementary-material" rid="pdf_001">Supplemental Fig. 2</xref>). These results suggested that the polymerase
activity and inhibitory effects of IFN induction of these proteins are not critical factors
in pathological differences of Mex4108 and Mex4487 shown in human cases and a cynomolgus
macaque model. Recently, several novel proteins encoded by polymerase genes and additional
functions of these proteins have been reported, suggesting the presence of additional
proteins and/or functions associated with pathogenesis [<xref rid="r17" ref-type="bibr">17</xref>, <xref rid="r25" ref-type="bibr">25</xref>, <xref rid="r30" ref-type="bibr">30</xref>]. To investigate the importance of PB2 or PA in virulence, the pathogenesis of
other recombinant viruses switching of PA and PB2 genes should be examined in animal models.
Also, the pathogenetic differences and molecular function of viruses will need to be
determined.</p><p>In this study, we showed that Mex4487 tends to induce severe pneumonia in infected
individuals, whereas Mex4108 has wide-spreading potential with mild disease. However, there
is no significant difference in most experiments, despite two Mexican isolates showing
heterogeneity in virulence in a cynomolgus macaque. It might be the limitation of the ferret
model, because animal models do not always reflect human cases. Whereas the clinical outcome
of two isolates was different, it may indicate that background and conditions of infected
individuals are important for determining the virulence as well as molecular determinants.
To understand the pathogenicity and transmissibility of viruses for preparation for future
risks, it is necessary to observe and accumulate the information of potential factors as
well as signature sequences to determine the phenotype of influenza viruses.</p></sec><sec id="s4"><title>CONFLICT OF INTERES</title><p> None to declare.</p></sec><sec sec-type="supplementary-material"><title>Supplementary Material</title><supplementary-material content-type="local-data" id="pdf_001"><caption><title>Supplement figure</title></caption><media mimetype="application" mime-subtype="pdf" xlink:href="jvms-79-1453-s001.pdf" orientation="portrait" xlink:type="simple" id="d35e529" position="anchor"></media></supplementary-material></sec></body><back><ack><p>We would like to thank Dr. Heinz Feldmann, Dr. Emmie de Wit, Dr. Vincent J
Munster, Dr. Dawn Clifton, Mr. Mark Dewald and Mr. Trenton Bushmaker, Laboratory of
Virology, DIR, NIAID, NIH for their technical support and intellectual contributions. We
also thank Dr. Dana Scott and members of Rocky Mountain Veterinary Branch, DIR, NIAID, NIH
for assistance with animal care. This research was supported by the Intramural Research
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HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/RBID.i -Sk "pubmed:28674309" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd \
| NlmPubMed2Wicri -a PandemieGrippaleV1
| This area was generated with Dilib version V0.6.34. |  |